Methodological Considerations When Using Polygenic Scores to Explore Parent-Offspring Genetic Nurturing Effects

<ns3:p>Background Research has begun to explore the effects of parental genetic nurturing on offspring outcomes using polygenic scores (PGSs). However, there are concerns regarding potential biases due to confounding when mediating parental phenotypes are included, and therefore it is imperative for researchers to be able to scrutinise their modelling and data assumptions. Methods We used simulations, symbolic computation, and data analysis to probe the source and extent of these biases. Regression and pathway models were estimated incorporating PGSs for both parents and offspring to explore direct (offspring PGS) and genetic nurturing (parental PGS) effects and parental phenotype effects on offspring phenotypes, using real and simulated data. Results Simulations demonstrated that models incorporating parent and offspring PGSs resulted in genetic nurturing effects that were unbiased. However, adding parental phenotypes as mediating variables results in biased positive estimates of parent phenotype mediated genetic nurturing effects and negative estimates of residual genetic nurturing effects unless the PGSs were simulated to capture the entirety of trait genetic variance. Analysis using symbolic computation helped clarify why the simulations yielded these results. Using real data, PGSs for depression, educational attainment, and height PGSs were generated in 2680 parent-offspring trios from the Generation Scotland: Scottish Family Health Study. Conclusion Relatively simple models combining parental and offspring PGSs can be used to detect genetic nurturing effects in complex traits. However, our findings suggest alternative methods should be utilised when aiming to identify mediating phenotypes and potentially modifiable parental nurturing effects.</ns3:p>